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Proteomic Analysis of GLUT4 Storage Vesicles Reveals Tumor Suppressor Candidate 5 (TUSC5) as a Novel Regulator of Insulin Action in Adipocytes

Abstract

Insulin signaling augments glucose transport by regulating glucose transporter 4 (GLUT4) trafficking from specialized intracellular compartments, termed GLUT4 storage vesicles (GSVs), to the plasma membrane. Proteomic analysis of GSVs by mass spectrometry revealed enrichment of 59 proteins in these vesicles. We measured reduced abundance of 23 of these proteins following insulin stimulation and assigned these as high confidence GSV proteins. These included established GSV proteins such as GLUT4 and insulin-responsive aminopeptidase, as well as six proteins not previously reported to be localized to GSVs. Tumor suppressor candidate 5 (TUSC5) was shown to be a novel GSV protein that underwent a 3.7-fold increase in abundance at the plasma membrane in response to insulin. siRNA-mediated knockdown of TUSC5 decreased insulin-stimulated glucose uptake, although overexpression of TUSC5 had the opposite effect, implicating TUSC5 as a positive regulator of insulin-stimulated glucose transport in adipocytes. Incubation of adipocytes with TNFalpha caused insulin resistance and a concomitant reduction in TUSC5. Consistent with previous studies, peroxisome proliferator-activated receptor (PPAR) gamma agonism reversed TNFalpha-induced insulin resistance. TUSC5 expression was necessary but insufficient for PPARgamma-mediated reversal of insulin resistance. These findings functionally link TUSC5 to GLUT4 trafficking, insulin action, insulin resistance, and PPARgamma action in the adipocyte. Further studies are required to establish the exact role of TUSC5 in adipocytes.

Type Journal
ISBN 1083-351X (Electronic) 0021-9258 (Linking)
Authors Fazakerley, D. J.; Naghiloo, S.; Chaudhuri, R.; Koumanov, F.; Burchfield, J. G.; Thomas, K. C.; Krycer, J. R.; Prior, M. J.; Parker, B. L.; Murrow, B. A.; Stockli, J.; Meoli, C. C.; Holman, G. D.; James, D. E.;
Garvan Authors Christopher Meoli
Publisher Name J BIOL CHEM
Published Date 2015-01-01 00:00:00
Published Volume 290
Published Issue 39
Published Pages 23528-42
URL http://www.ncbi.nlm.nih.gov/pubmed/26240143
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?13157_13418/15_Fazakerley_JBC.pdf